In search of hormones and drugs, which stimulate the epidermal cyclic AMP system, we have found four distinct categories: Beta-adrenergic agonists, histamine H2, adenosine (and adenine nucleotides) and prostaglandins (E series). Each of these receptors becomes unresponsive to further stimulation by its specific stimulator upon activation (refractoriness). Guanylate cyclase is activated by histamine H1, and epidermal growth factor (EGF). When the skin is traumatized, cyclic AMP rapidly rises to 5-10 times its normal level while cyclic GMP falls to 10-20% of their in vivo levels (ischemia effects). In the epidermal outgrowth culture system, agents which increase cyclic AMP do inhibit the epidermal outgrowth and mitotic activity. Cyclic GMP does increase outgrowth at a particular concentration. Histamine, which elevates both cyclic nucleotides, has a biphasic action depending on its concentration. These findings imply that these nucleotides do act as one of the controls of epidermal proliferation. The action of cyclic GMP is not accompanied by detectably increased phosphorylation of epidermal proteins. On the other hand, epidermal growth factor (EGF) action which also enhances epidermal outgrowth is characterized by an increased protein phosphorylation which precedes any increase in cellular cyclic GMP. We conclude that the action of EGF is independent of the cyclic nucleotide system. Possible abnormalities in the guanylate cyclase system in psotiatic skin is currently being sought.